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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness.
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Antitrypanosomal activity of fexinidazole, a new oral nitroimidazole drug candidate for treatment of sleeping sickness.

机译：新型口服硝基咪唑药物候选药物fexinidazole的抗胰蛋白酶活性，可用于治疗昏睡病。

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Fexinidazole is a 5-nitroimidazole drug currently in clinical development for the treatment of human sleeping sickness (human African trypanosomiasis [HAT]), caused by infection with species of the protozoan parasite Trypanosoma brucei. The compound and its two principal metabolites, sulfoxide and sulfone, have been assessed for their ability to kill a range of T. brucei parasite strains in vitro and to cure both acute and chronic HAT disease models in the mouse. The parent molecule and both metabolites have shown trypanocidal activity in vitro in the 0.7-to-3.3 muM (0.2-to-0.9 mug/ml) range against all parasite strains tested. In vivo, fexinidazole is orally effective in curing both acute and chronic diseases in the mouse at doses of 100 mg/kg of body weight/day for 4 days and 200 mg/kg/day for 5 days, respectively. Pharmacokinetic data indicate that it is likely that the sulfoxide and sulfone metabolites provide most, if not all, of the in vivo killing activity. Fexinidazole and its metabolites require up to 48 h exposure in order to induce maximal trypanocidal efficacy in vitro. The parent drug and its metabolites show no in vitro cross-reactivity in terms of trypanocidal activity with either themselves or other known trypanocidal drugs in use in humans. The in vitro and in vivo antitrypanosomal activities of fexinidazole and its two principal metabolites provide evidence that the compound has the potential to be an effective oral treatment for both the T. b. gambiense and T. b. rhodesiense forms of human sleeping sickness and both stages of the disease.
机译：非辛达唑是一种5-硝基咪唑药物，目前正处于临床开发中，用于治疗由原生动物寄生虫布鲁氏锥虫感染引起的人类昏睡病（非洲锥虫病[HAT]）。已评估了该化合物及其两种主要代谢物亚砜和砜的体外杀灭一系列布鲁氏杆菌寄生虫菌株以及治愈小鼠急性和慢性HAT疾病模型的能力。母体分子和两种代谢物均在体外对所有测试的寄生虫菌株表现出0.7-3.3μM（0.2-0.9马克杯/毫升）的锥虫活性。在体内，非辛达唑口服剂量分别为100 mg / kg体重/天，4天和200 mg / kg /天，5天，可有效治愈小鼠的急性和慢性疾病。药代动力学数据表明，亚砜和砜代谢物有可能提供大部分（即使不是全部）体内杀伤活性。 Fexinidazole及其代谢物需要长达48 h的暴露时间才能在体外诱导最大的锥虫杀灭效果。母体药物及其代谢产物与自身或其他已知的用于人类的锥虫活性药物在锥虫活性方面均无体外交叉反应性。非辛达唑及其两种主要代谢产物的体外和体内抗胰锥虫活性提供了证据，表明该化合物具有对T. b。进行有效口服治疗的潜力。 gambiense和T. b。罗得岛型人类昏睡病和疾病的两个阶段。

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